title: The effect of the frequency and duration of PSA measurement on PSA doubling time calculations in men with biochemically recurrent prostate cancer.
abstract: BACKGROUND
  PSA doubling time (PSADT) is an attractive intermediate end point for assessing novel therapies in biochemically recurrent prostate cancer (BRPC). This study explores whether PSADT calculations are influenced by frequency/duration of PSA measurements, and whether statistical variability leads investigators to find false significant results.
  
  
  METHODS
  In retrospective analyses of two BRPC cohorts: Johns Hopkins Hospital (JHH) patients who deferred therapy and placebo patients on a randomized clinical trial (RCT), we calculated changes in PSADT from early measurements to later measurements using subsets of available PSAs for patients with ≥6 and ≥9 PSAs. We simulated hypothetical single-arm trials using randomly selected, 50-patient subsets and simulated two-arm RCTs.
  
  
  RESULTS
  JHH cohort (n=205) had median follow-up 58 months, median age 61 years and median Gleason 7. PSA variability changed with duration of PSA measurement as median within-patient PSADT increases for men with >6 PSAs ranged from 1.0 to 1.4 months by PSA subset while increases for men with ≥9 PSAs ranged from 3.9 to 4.1 months. Frequency of measurement did not change PSA variability as PSADT increase was unchanged when odd values were used instead of all values. Approximately 30% of JHH men experienced >200% increases in PSADT. Up to 62% of 50-patient single-arm simulations detected a significant PSADT change, whereas simulated RCTs did not. Results were supported in the RCT placebo cohort; 46% of patients experienced PSADT increases >200%.
  
  
  CONCLUSIONS
  These data suggest that calculated PSADT in BRPC may naturally increase over time in the absence of therapy and may be influenced by duration of PSA follow-up. As a result, single-arm trials could show false significant increases despite the lack of active treatment of these patients. Placebo-controlled RCTs including clinical end points are recommended to screen novel agents in men with BRPC to mitigate bias because of natural PSADT variability.
authors.affiliation: Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Paller
authors.affiliation: Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Olatoye
authors.affiliation: Alfred I DuPont Hospital for Children, Wilmington, DE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Xie
authors.affiliation: Division of Oncology Biostatistics and Bioinformatics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Denmeade
authors.affiliation: Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Eisenberger
authors.affiliation: Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Carducci
authors.affiliation: Division of Oncology Biostatistics and Bioinformatics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Rosner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D017430:Prostate-Specific Antigen